Cetrotide® 0.25 mg (cetrorelix acetate) for InjectionFOR SUBCUTANEOUS USE ONLY

DESCRIPTION

Cetrotide® (cetrorelix acetate for injection) is a
synthetic decapeptide with gonadotropin-releasing hormone (GnRH) antagonistic
activity. Cetrorelix acetate is an analog of native GnRH with substitutions of
amino acids at positions 1, 2, 3, 6, and 10. The molecular formula is
Acetyl-D-3-(2´-naphtyl)-alanine-D-4-chlorophenylalanine-D-3-(3´-pyridyl)-alanine-L-serine-L-tyrosine-D-citruline-L-leucine-L-arginine-L-proline-D-alanine-amide,
and the molecular weight is 1431.06, calculated as the anhydrous free base. The
structural formula is as follows:

INDICATIONS

Cetrotide® (cetrorelix acetate for injection) is
indicated for the inhibition of premature LH surges in women undergoing
controlled ovarian stimulation.

DOSAGE AND ADMINISTRATION

Ovarian stimulation therapy with gonadotropins (FSH, hMG)
is started on cycle Day 2 or 3. The dose of gonadotropins should be adjusted
according to individual response. Cetrotide® (cetrorelix acetate for injection)
0.25 mg may be administered subcutaneously once daily during the early- to
mid-follicular phase.

Cetrotide® 0.25 mg is administered on either stimulation
day 5 (morning or evening) or day 6 (morning) and continued daily until the day
of hCG administration.

When assessment by ultrasound shows a sufficient number
of follicles of adequate size, hCG is administered to induce ovulation and
final maturation of the oocytes. No hCG should be administered if the ovaries
show an excessive response to the treatment with gonadotropins to reduce the
chance of developing ovarian hyperstimulation syndrome (OHSS).

Administration

Cetrotide® 0.25 mg can be administered by the patient
herself after appropriate instructions by her doctor.

Directions for using Cetrotide® 0.25 mg with
the enclosed needles and pre-filled syringe:

Wash hands thoroughly with soap and water.

Flip off the plastic cover of the vial and wipe the
aluminum ring and the rubber stopper with an alcohol swab.

Twist the injection needle with the yellow mark (20
gauge) on the pre-filled syringe.

Push the needle through the center of the rubber stopper
of the vial and slowly inject the solvent into the vial.

Leaving the syringe in the vial, gently swirl the vial
until the solution is clear and without residues. Avoid forming bubbles.

Draw the total contents of the vial into the syringe. If
necessary, invert the vial and pull back the needle as far as needed to
withdraw the entire contents of the vial.

Replace the needle with the yellow mark by the injection
needle with the grey mark (27 gauge).

Invert the syringe and push the plunger until all air
bubbles have been expelled.

Choose an injection site in the lower abdominal area,
preferably around, but staying at least one inch away from the navel. Choose a
different injection site each day to minimize local irritation. Use the second
alcohol swab to clean the skin at the injection site and allow alcohol to dry.
Gently pinch up the skin surrounding the site of injection.

Inject the prescribed dose as directed by your doctor,
nurse or pharmacist.

Use the syringe and needles only once. Dispose of the
syringe and needles properly after use. If available, use a medical waste
container for disposal.

HOW SUPPLIED

Cetrotide® (cetrorelix acetate for injection) 0.25 mg is
available in a carton of one packaged tray (NDC 44087-1225-1).

SIDE EFFECTS

The safety of Cetrotide® (cetrorelix acetate for
injection) in 949 patients undergoing controlled ovarian stimulation in
clinical studies was evaluated. Women were between 19 and 40 years of age
(mean: 32). 94.0% of them were Caucasian. Cetrotide® was given in doses ranging
from 0.1 mg to 5 mg as either a single or multiple dose.

Table 3 shows systemic adverse events, reported in
clinical studies without regard to causality, from the beginning of Cetrotide® treatment
until confirmation of pregnancy by ultrasound at an incidence ≥ 1% in
Cetrotide® treated subjects undergoing COS.

Table 3: Adverse Events in ≥ 1%

(WHO preferred term)

Cetrotide®
N=949
% (n)

Ovarian Hyperstimulation Syndrome*

3.5 (33)

Nausea

1.3 (12)

Headache

1.1 (10)

* Intensity moderate or severe, or WHO Grade II or III,
respectively

Local site reactions (e.g. redness, erythema, bruising,
itching, swelling, and pruritus) were reported. Usually, they were of a
transient nature, mild intensity and short duration. During post-marketing
surveillance, rare cases of hypersensitivity reactions including anaphylactoid
reactions have been reported.

Two stillbirths were reported in Phase 3 studies of
Cetrotide®.

Congenital Anomalies

Clinical follow-up studies of 316 newborns of women
administered Cetrotide® were reviewed. One infant of a set of twin neonates was
found to have anencephaly at birth and died after four days. The other twin was
normal. Developmental findings from ongoing baby follow-up included a child
with a ventricular septal defect and another child with bilateral congenital glaucoma.

The causal relationship between the reported anomalies
and Cetrotide® is unknown. Multiple factors, genetic and others (including, but
not limited to ICSI, IVF, gonadotropins, and progesterone) make causal
attribution difficult to study.

DRUG INTERACTIONS

No formal drug interaction studies have been performed
with Cetrotide®.

WARNINGS

Cetrotide® (cetrorelix acetate for injection) should be
prescribed by physicians who are experienced in fertility treatment. Before
starting treatment with Cetrotide®, pregnancy must be excluded (seeCONTRAINDICATIONS and PRECAUTIONS).

PRECAUTIONS

General

Cases of hypersensitivity reactions, including
anaphylactoid reactions with the first dose, have been reported during
post-marketing surveillance (see ADVERSE REACTIONS). A severe
anaphylactic reaction associated with cough, rash, and hypotension, was
observed in one patient after seven months of treatment with Cetrotide® (10
mg/day) in a study for an indication unrelated to infertility.

Special care should be taken in women with signs and
symptoms of active allergic conditions or known history of allergic predisposition.
Treatment with Cetrotide® is not advised in women with severe allergic
conditions.

Information for Patients

Prior to therapy with Cetrotide® (cetrorelix acetate for
injection), patients should be informed of the duration of treatment and
monitoring procedures that will be required. The risk of possible adverse
reactions should be discussed (see ADVERSE REACTIONS). Cetrotide® should
not be prescribed if a patient is pregnant.

If Cetrotide® is prescribed to patients for
self-administration, information for proper use is given in the Patient Leaflet (see below).

Laboratory Tests

After the exclusion of preexisting conditions, enzyme
elevations (ALT, AST, GGT, alkaline phosphatase) were found in 1-2% of patients
receiving Cetrotide® during controlled ovarian stimulation. The elevations
ranged up to three times the upper limit of normal. The clinical significance
of these findings was not determined.

During stimulation with human menopausal gonadotropin,
Cetrotide® had no notable effects on hormone levels aside from inhibition of LH
surges.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term carcinogenicity studies in animals have not
been performed with cetrorelix acetate. Cetrorelix acetate was not genotoxic in
vitro (Ames test, HPRT test, chromosome aberration test) or in vivo (chromosome
aberration test, mouse micronucleus test). Cetrorelix acetate induced
polyploidy in CHL-Chinese hamster lung fibroblasts, but not in V79-Chinese
hamster lung fibroblasts, cultured peripheral human lymphocytes or in an in
vitro micronucleus test in the CHL-cell line. Treatment with 0.46 mg/kg
cetrorelix acetate for 4 weeks resulted in complete infertility in female rats
which was reversed 8 weeks after cessation of treatment.

Pregnancy Category X

When administered to rats for the first seven days of
pregnancy, cetrorelix acetate did not affect the development of the implanted
conceptus at doses up to 38 μg/kg (approximately 1 times the recommended
human therapeutic dose based on body surface area). However, a dose of 139
μg/kg (approximately 4 times the human dose) resulted in a resorption rate
and a postimplantation loss of 100%. When administered from day 6 to near term
to pregnant rats and rabbits, very early resorptions and total implantation
losses were seen in rats at doses from 4.6 μg/kg (0.2 times the human
dose) and in rabbits at doses from 6.8 μg/kg (0.4 times the human dose).
In animals that maintained their pregnancy, there was no increase in the
incidence of fetal abnormalities.

The fetal resorption observed in animals is a logical
consequence of the alteration in hormonal levels effected by the
antigonadotrophic properties of Cetrotide®, which could result in fetal loss in
humans as well. Therefore, this drug should not be used in pregnant women.

Nursing Mothers

It is not known whether Cetrotide® is excreted in human
milk. Because many drugs are excreted in human milk, and because the effects of
Cetrotide® on lactation and/or the breast-fed child have not been determined,
Cetrotide® should not be used by nursing mothers.

Geriatric Use

OVERDOSE

There have been no reports of overdosage with Cetrotide® 0.25
mg or 3 mg in humans. Single doses up to 120 mg Cetrotide® have been well
tolerated in patients treated for other indications without signs of
overdosage.

CONTRAINDICATIONS

Cetrotide® (cetrorelix acetate for injection) is
contraindicated under the following conditions:

CLINICAL PHARMACOLOGY

GnRH induces the production and release of luteinizing
hormone (LH) and follicle stimulating hormone (FSH) from the gonadotrophic
cells of the anterior pituitary. Due to a positive estradiol (E2) feedback at
midcycle, GnRH liberation is enhanced resulting in an LH-surge. This LH-surge
induces the ovulation of the dominant follicle, resumption of oocyte meiosis
and subsequently luteinization as indicated by rising progesterone levels.

Cetrotide® competes with natural GnRH for binding to
membrane receptors on pituitary cells and thus controls the release of LH and
FSH in a dose-dependent manner. The onset of LH suppression is approximately
one hour with the 3 mg dose and two hours with the 0.25 mg dose. This
suppression is maintained by continuous treatment and there is a more
pronounced effect on LH than on FSH. An initial release of endogenous
gonadotropins has not been detected with Cetrotide®, which is consistent with
an antagonist effect.

The effects of Cetrotide® on LH and FSH are reversible
after discontinuation of treatment. In women, Cetrotide® delays the LH-surge,
and consequently ovulation, in a dose-dependent fashion. FSH levels are not
affected at the doses used during controlled ovarian stimulation. Following a
single 3 mg dose of Cetrotide®, duration of action of at least 4 days has been
established. A dose of Cetrotide® 0.25 mg every 24 hours has been shown to
maintain the effect.

Pharmacokinetics

The pharmacokinetic parameters of single and multiple
doses of Cetrotide® (cetrorelix acetate for injection) in adult healthy female
subjects are summarized in Table 1.

Table 1: Pharmacokinetic parameters of Cetrotide®
following 3 mg single or 0.25 mg single and multiple (daily for 14 days)
subcutaneous (sc) administration.

Absorption

Cetrotide® is rapidly absorbed following subcutaneous
injection, maximal plasma concentrations being achieved approximately one to
two hours after administration. The mean absolute bioavailability of Cetrotide®
following subcutaneous administration to healthy female subjects is 85%.

Distribution

The volume of distribution of Cetrotide® following a
single intravenous dose of 3 mg is about 1 l/kg. In vitro protein binding to
human plasma is 86%.

Cetrotide® concentrations in follicular fluid and plasma
were similar on the day of oocyte pick-up in patients undergoing controlled
ovarian stimulation. Following subcutaneous administration of Cetrotide® 0.25
mg and 3 mg, plasma concentrations of cetrorelix were below or in the range of
the lower limit of quantitation on the day of oocyte pick-up and embryo
transfer.

Metabolism

After subcutaneous administration of 10 mg Cetrotide® to
females and males, Cetrotide® and small amounts of (1-9), (1-7), (1-6), and
(1-4) peptides were found in bile samples over 24 hours.

In in vitro studies, Cetrotide® was stable against phase
I- and phase II-metabolism. Cetrotide® was transformed by peptidases, and the
(1-4) peptide was the predominant metabolite.

Excretion

Following subcutaneous administration of 10 mg cetrorelix
to males and females, only unchanged cetrorelix was detected in urine. In 24
hours, cetrorelix and small amounts of the (1-9), (1-7), (1-6), and (1-4)
peptides were found in bile samples. 2-4% of the dose was eliminated in the
urine as unchanged cetrorelix, while 5-10% was eliminated as cetrorelix and the
four metabolites in bile. Therefore, only 7-14% of the total dose was recovered
as unchanged cetrorelix and metabolites in urine and bile up to 24 hours. The
remaining portion of the dose may not have been recovered since bile and urine
were not collected for a longer period of time.

Special Populations

Pharmacokinetic investigations have not been performed
either in subjects with impaired renal or liver function, or in the elderly, or
in children (see PRECAUTIONS).

Pharmacokinetic differences in different races have not
been determined.

There is no evidence of differences in pharmacokinetic
parameters for Cetrotide® between healthy subjects and patients undergoing
controlled ovarian stimulation.

Drug-Drug Interactions

No formal drug-drug interaction studies have been
performed with Cetrotide® (seePRECAUTIONS).

Clinical Studies

Seven hundred thirty two (732) patients were treated with
Cetrotide® (cetrorelix acetate for injection) in five (two Phase 2 dose-finding
and three Phase 3) clinical trials. The clinical trial population consisted of
Caucasians (95.5%) and Black, Asian, Arabian and others (4.5%). Women were
between 19 and 40 years of age (mean: 32). The studies excluded subjects with
polycystic ovary syndrome (PCOS), subjects with low or no ovarian reserve, and
subjects with stage III-IV endometriosis.

Two dose regimens were investigated in these clinical
trials, either a single dose per treatment cycle or multiple dosing. In the
Phase 2 studies, a single dose of 3 mg was established as the minimal effective
dose for the inhibition of premature LH surges with a protection period of at
least 4 days. When Cetrotide® is administered in a multidose regimen, 0.25 mg
was established as the minimal effective dose. The extent and duration of
LH-suppression is dose dependent.

In the Phase 3 program, efficacy of the single 3 mg dose
regimen of Cetrotide® and the multiple 0.25 mg dose regimen of Cetrotide® was
established separately in two adequate and well controlled clinical studies
utilizing active comparators. A third non-comparative clinical study evaluated
only the multiple 0.25 mg dose regimen of Cetrotide®. The ovarian stimulation
treatment with recombinant FSH or human menopausal gonadotropin (hMG) was
initiated on day 2 or 3 of a normal menstrual cycle. The dose of gonadotropins was
administered according to the individual patient's disposition and response.

In the single dose regimen study, Cetrotide®3 mg was
administered on the day of controlled ovarian stimulation when adequate
estradiol levels (400 pg/mL) were obtained, usually on day 7 (range day
5-12).If hCG was not given within 4 days of the 3 mg dose of Cetrotide®, then
0.25 mg of Cetrotide® was administered daily beginning 96 hours after the 3 mg
injection until and including the day of hCG administration.

In the two multiple dose regimen studies, Cetrotide®0.25
mg was started on day5 or 6 of COS. Both gonadotropins and Cetrotide® were
continued daily (multiple dose regimen) until the injection of human chorionic
gonadotropin (hCG).

In addition to IVF and ICSI, one pregnancy was obtained
after intrauterine insemination. In the five Phase 2 and Phase 3 clinical
trials, 184 pregnancies have been reported out of a total of 732 patients
(including 21 pregnancies following the replacement of frozen-thawed embryos).

In the 3 mg regimen, 9 patients received an additional
dose of 0.25 mg of Cetrotide® and two other patients received two additional
doses of 0.25 mg Cetrotide®. The median number of days of Cetrotide® multiple
dose treatment was 5 (range 1-15) in both studies.

No drug related allergic reactions were reported from
these clinical studies.

PATIENT INFORMATION

Cetrotide® 0.25 mg

Active ingredient: cetrorelix acetate

Summary

Cetrotide® blocks the effects of a natural hormone,
called gonadotropin-releasing hormone (GnRH). GnRH controls the secretion of
another hormone, called luteinizing hormone (LH), which induces ovulation
during the menstrual cycle. During hormone treatment for ovarian stimulation,
premature ovulation may lead to eggs that are not suitable for fertilization.
Cetrotide® blocks such undesirable premature ovulation.

Uses

Cetrotide® is used to prevent premature ovulation during
controlled ovarian stimulation.

General Cautions

Do not use Cetrotide® if you

have kidney disease

are allergic to cetrorelix acetate, mannitol or exogenous peptide hormones (medicines similar to Cetrotide®) or

are pregnant, or think that you might be pregnant, or if
you are breast-feeding.

Consult your doctor before taking Cetrotide® if you have
had severe allergic reactions.

Proper Use

Ovarian stimulation therapy is started on cycle Day 2 or
3. Cetrotide® 0.25 mg is injected under the skin once daily , as directed by
your physician. When an ultrasound examination shows that you are ready,
another drug (hCG) is injected to induce ovulation.

How should you use Cetrotide®?

You may self-inject Cetrotide® after special instruction
from your doctor.

To fully benefit from Cetrotide®, please read carefully
and follow the instructions given below, unless your doctor advises you
otherwise.

Cetrotide® is for injection under the skin of the lower
abdominal area, preferably around, but staying at least one inch away from the
belly button. Choose a different injection site each day to minimize local
irritation.

Dissolve Cetrotide® powder only with the water contained
in the pre-filled syringe. Do not use a Cetrotide® solution if it contains
particles or if it is not clear.

Before you inject Cetrotide® yourself, please read the
following instructions carefully:

Directions for using Cetrotide® 0.25 mg with
the enclosed needles and pre-filled syringe:

1. Wash your hands thoroughly with soap and water.

2. On a clean flat surface, lay out everything you need
(one vial of powder, one pre-filled syringe, one injection needle with a yellow
mark, one injection needle with a grey mark, and two alcohol wipes).

3. Flip off the plastic cover of the vial. Wipe the
aluminum ring and the rubber stopper with an alcohol wipe.

4. Take the injection needle with the yellow mark and
remove the wrapping. Take the pre-filled syringe and remove the cover. Twist
the needle on the syringe and remove the cover of the needle.

5. Push the needle through the center of the rubber
stopper of the vial. Inject the water into the vial by slowly pushing down on
the plunger o f the syringe.

6. Leave the syringe in the vial. Gently shake the vial
until the solution is clear and without residue. Avoid forming bubbles during
dissolution.

7. Draw the total contents of vial, pull back the needle
until the opening of the needle is the vial into the syringe. If liquid is left
in the vial, invert the just inside the stopper. If you look from the side
through the gap in the stopper, you can control the movement of the needle and
the liquid. It is important to withdraw the entire contents of the vial.

8. Detach the syringe from the needle and lay down the
syringe. Take the injection needle with the grey mark and remove its wrapping.
Twist the needle on the syringe and remove the cover of the needle.

9. Invert the syringe and push the plunger until all air
bubbles have been pushed out. Do not touch the needle or allow the needle to
touch any surface.

10. Choose an injection site in the lower abdominal area,
preferably around, but at least one inch away from the belly button. Choose a
different injection site each day to minimize local irritation. Take the second
alcohol wipe and clean the skin at the injection site and allow alcohol to dry.
Inject the prescribed dose as directed by your doctor, nurse or pharmacist.

11. Use the syringe and needles only once. Dispose of the
syringe and needles immediately after use (put the covers on the needles to
avoid injury). A medical waste container should be used of or disposal.

SPECIAL ADVICE

What do you do if you have used too much Cetrotide®?

Contact your doctor in case of overdosage immediately to
check whether an adjustment of the further ovarian stimulation procedure is
required.

Possible Side Effects

Mild and short lasting reactions may occur at the
injection site like reddening, itching, and swelling. Nausea and headache have
also been reported.

Call your doctor if you have any side effect not
mentioned in this leaflet or if you are unsure about the effect of this
medicine.

Storage

How is Cetrotide® to be stored?

Store Cetrotide® in a cool dry place protected from
excess moisture and heat.

Store Cetrotide® 0.25 mg in the refrigerator at 2-8°C
(36-46°F). Keep the packaged tray in the outer carton in order to protect it
from light.

How long may Cetrotide® be stored?

Do not use the Cetrotide® powder or the pre-filled
syringe after the expiration date, which is printed on the labels and on the
carton, and dispose of the vial and the syringe properly.

How long can you keep Cetrotide® after preparation of
the solution?

The solution should be used immediately after
preparation.

Store the medicine out of the reach of children.

If you suspect that you may have taken more than the
prescribed dose of this medicine, contact your doctor immediately. This
medicine was prescribed for your particular condition. Do not use it for
another condition or give the drug to others.

This leaflet provides a summary of the information about
Cetrotide®. Medicines are sometimes prescribed for uses other than those listed
in the Leaflet. If you have any questions or concerns, or want more information
about Cetrotide®, contact your doctor or pharmacist.

This Leaflet has been approved by the U.S. Food and Drug
Administration.

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.